Despite decades of research on blood pressure (BP) physiology, our understanding of the biological basis of clinical hypertension (HTN) is still wanting. Recent, genome-wide association studies (GWAS) in ~70,000 individuals of European ancestry have been successful in identifying common variants at 29 loci that explain 2.5% of the inter-individual variation in systolic- (SBP) and diastolic- (DBP) blood pressure, with concomitant effects on HTN. Similar studies are ongoing using pulse (PP) and mean arterial (MAP) pressure. These putative genes provide new targets for understanding essential hypertension but the vast majority of the genetic variation in HTN susceptibility remains elusive. We propose a comprehensive study to explore the role of rare and common genomic variation on SBP, DBP and HTN in individuals of European (EA) and African (AA) American ancestry using contemporary genomic methods including exome sequencing and novel statistical methods that include gene-gene and gene-environment interactions. This study includes DNA samples, genotypes and phenotypes from the ARIC (Atherosclerosis Risk in Communities), FBPP (Family Blood Pressure Program), WHI (Women's Health Initiative) and CARDIA (Coronary Artery Risk Development In Young Adults) cohorts, with replication of findings using data and meta-analysis from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), CARe (Candidate-gene Association Resource), ICBP (International Consortium of Blood Pressure GWAS) and RFGEH (Research Program in Genes, Environment and Health) consortia/studies. We will explore: (1) A third generation BP and HTN GWAS using all known polymorphic markers;(2) a first generation BP and HTN EWAS (exome-wide association study) using all identifiable rare variants;and, (3) gene-gene and gene-environment interactions in BP and HTN variability. ! PUBLIC HEALTH RELEVANCE: Genome-wide association studies for the different blood pressure traits, that are intermediate phenotypes for essential hypertension and its consequences for target organ damage, have recently been successful with 29 loci identified but explaining only 2.5% of the phenotypic variance upon meta-analyses of 70,000 samples of European ancestry. In this proposal, we conduct computational and molecular genetic experiments to increase gene discovery by studying all polymorphisms in the human genome, assessing the role of rare variants in the exome and the role of gene- environment interactions. Our aims are to improve the molecular genetic understanding of blood pressure regulation and inter-individual variation on hypertension risk.